Aggregated alpha-synuclein transcriptionally activates pro-inflammatory canonical and non-canonical NF-κB signaling pathways in peripheral monocytic cells

• DOI: 10.1016/j.molimm.2022.12.006
• Publication Date: 2022-12-25T02:41:34Z
• Authors: Frank Bearoff; Dhruva Dhavale; Paul Kotzbauer; Sandhya Kortagere
• Keywords: Inflammation; 0303 health sciences; 03 medical and health sciences; Neuroinflammatory Diseases; alpha-Synuclein; NF-kappa B; Humans; Parkinson Disease; Genome-Wide Association Study; Signal Transduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by chronic neuroinflammation, loss of dopaminergic neurons in the substantia nigra, and in several cases accumulation of alpha-synuclein fibril (α-syn) containing Lewy-bodies (LBs). Peripheral inflammation may play a causal role in inducing and perpetuating neuroinflammation in PD and accumulation of fibrillar α-syn has been reported at several peripheral sites including the gut and liver. Peripheral fibrillar α-syn may induce activation of monocytes via recognition by toll-like receptors (TLRs) and stimulation of downstream NF-κB signaling; however, the specific mechanism by which this occurs is not defined. In this study we utilized the THP-1 monocytic cell line to model the peripheral transcriptional response to preformed fibrillar (PFF) α-syn. Compared to monomeric α-syn, PFF α-syn displays overt inflammatory gene upregulation and pathway activation including broad pan-TLR signaling pathway activation and increases in TNF and IL1B gene expression. Notably, the non-canonical NF-κB signaling pathway gene and PD genome wide association study (GWAS) candidate NFKB2 was upregulated. Additionally, non-canonical NF-κB activation-associated RANK and CD40 pathways were also upregulated. Transcriptional-phenotype analysis suggests PFFs induce transcriptional programs associated with differentiation of monocytes towards macrophages and osteoclasts via non-canonical NF-κB signaling as a potential mechanism in which myeloid/monocyte cells may contribute to peripheral inflammation and pathogenesis in PD.